Human consumption of ephedrine and caffeine in some ephedra containing supplements has been associated with a number of adverse effects including changes in the electrocardiogram (ECG), myocardial infarction, hyperthermia, and in rare instances, death. The purpose of this study was to investigate the potential mechanisms associated with the cardiotoxicity of combined ephedrine and caffeine ingestion. Seven and 14 week old Fischer 344 rats treated with ephedrine in combination with caffeine exhibited increases in heart rate, temperature and QTc interval. Of the 14 week old rats treated with the highest dose (25 mg/kg ephedrine plus 30 mg/kg caffeine), 57% died within 3-5 hours of treatment, while none of the similarly treated 7 week old rats nor any of the rats treated with lower doses or with vehicle, died. In both the 7 week old and 14 week old rats, all ephedrine plus caffeine treatments resulted in a significant increase in heart rate (HR) compared to baseline measurements at both one and three hours. However, the 14 week old, but not the 7 week old, animals treated with highest dose exhibited significantly higher HR at three hours than animals treated with any of the other concentrations of ephedrine plus caffeine. Furthermore, the 14 week old rats that died showed a higher HR (one and three hours after treatment) and an increased temperature (one hour after treatment) than the 14 week old rats that lived. Histopathological studies suggested interstitial hemorrhage and myofiber necrosis. Higher expression of ?1-adrenergic receptor and uncoupling protein 2 were found in 14 week old rats. Histopathological studies suggested interstitial hemorrhage and myofiber necrosis. This study showed enhanced susceptibility to ephedrine plus caffeine in 14 week old rats compared to 7 week old rats The greater susceptibility in the 14 week old rats was associated with increases in body temperature and heart rate, expression of UCP 2 and myocardial necrosis. We have recently undertaken a study on AZT (zidovudine) an antiretroviral drug and the cardiotoxicity that is associated with it. Rats were treated for 2 or 4 weeks with AZT, at which time we harvested RNA from the hearts of these animals. Microarrays were run on the 2 week samples and the most striking feature from these arrays was the change in multiple genes associated with the circadian clock. Real time PCR confirmed many of the changes, as well as some changes in the 4 week samples and some changes in genes that have been identified as being circadian regulated in the heart.